Faculty Bibliography

Karim Nader changed the course of memory research by reviving interest in the mostly forgotten topic of post-retrieval manipulations of memory. In this paper I summarize the events leading up to his ground-breaking study in my lab on so-called memory reconsolidation, and the effects of that study on the field.

Fragile X Syndrome (FXS) is a neurodevelopmental disorder and the most common monogenic cause of intellectual disability, autism spectrum disorders (ASDs) and anxiety disorders. Loss of fragile x mental retardation protein (FMRP) results in disruptions of synaptic development during a critical period (CP) of circuit formation in the basolateral amygdala (BLA). However, it is unknown how these alterations impact microcircuit development and function. Using a combination of electrophysiologic and behavioral approaches in both male (Fmr1-/y) and female (Fmr1-/-) mice, we demonstrate that principal neurons (PNs) in the Fmr1KO BLA exhibit hyperexcitability during a sensitive period in amygdala development. This hyperexcitability contributes to increased excitatory gain in fear-learning circuits. Further, synaptic plasticity is enhanced in the BLA of Fmr1KO mice. Behavioral correlation demonstrates that fear-learning emerges precociously in the Fmr1KO mouse. Early life THIP intervention ameliorates fear-learning in Fmr1KO mice. These results suggest that CP plasticity in the amygdala of the Fmr1KO mouse may be shifted to earlier developmental timepoints.SIGNIFICANCE STATEMENTIn these studies we identify early developmental alterations in principal neurons in the FXS BLA. We show that as early as P14, excitability and feed-forward excitation, and synaptic plasticity is enhanced in Fmr1KO lateral amygdala. This correlates with precocious emergence of fear-learning in the Fmr1KO mouse. Early life THIP intervention restores CP plasticity in WT mice and ameliorates fear-learning in the Fmr1KO mouse.

The hippocampal CA2 region, an area important for social memory, has been suspected to play a role in temporal lobe epilepsy (TLE) because of its resistance to degeneration observed in neighboring CA1 and CA3 regions in both humans and rodent models of TLE. However, little is known about whether alterations in CA2 properties promote seizure generation or propagation. Here, we addressed the role of CA2 using the pilocarpine-induced status epilepticus model of TLE. Ex vivo electrophysiological recordings from acute hippocampal slices revealed a set of coordinated changes that enhance CA2 PC intrinsic excitability, reduce CA2 inhibitory input, and increase CA2 excitatory output to its major CA1 synaptic target. Moreover, selective chemogenetic silencing of CA2 pyramidal cells caused a significant decrease in the frequency of spontaneous seizures measured in vivo. These findings provide the first evidence that CA2 actively contributes to TLE seizure activity and may thus be a promising therapeutic target.

Introduction: This exploratory study sought to examine the extent to which family-level factors are associated with disruptive behavioral disorder (DBD) symptoms, including oppositional defiant disorder (ODD) and conduct disorder (CD) among school children in Uganda, a low-resource country in SSA. The examination of key influences within the SSA context is important to guide needed investments in mental health care and family-level support. Importantly, identifying families at higher risk can inform the development of contextualized family interventions that reinforce positive parenting practices. Method: We analyzed baseline data (N = 2110) from the NIH-funded Strengthening Mental health And Research Training in Africa (SMART Africa) scale-up study in Southwestern Uganda. Children aged 8-13 and their caregivers were recruited from 30 public primary schools. DBDs were examined using the DBD rating scale, Iowa Conners, and Impairment scales. Logistic regression analysis using cluster adjusted robust standard errors to adjust for within-school clustering was conducted to assess the association between DBD symptoms and family-level factors, including parenting practices, marital status, and family size. Results: Results indicate that poor parental supervision (OR = 1.17; CI: 1.13, 1.21; P < .001), divorced families (OR = 1.33; CI: 1.03, 1.72; P < .05), and widowed families (OR = 1.48; CI: 1.10, 2.00; P < .01) were associated with higher DBD symptoms among children. On the other hand, caregiver age (OR = 0.99; CI: 0.98, 0.99; P < .01) was associated with lower DBD symptoms among children. Moreover, caregiver employment and parental education were not statistically significant in the model. Conclusion: Findings from the study reveal an association between family-level factors and behavioral difficulties among children in Uganda suggesting that divorced and widowedfamilies may benefit from additional support in caring for children. Moreover, caregivers may also benefit from programs that provide tools for effective parental supervision. (PsycInfo Database Record (c) 2022 APA, all rights reserved)

PURPOSE: The prognosis for SHH-medulloblastoma (MB) patients with Li-Fraumeni syndrome (LFS) is poor. Due to lack of comprehensive data for these patients, it is challenging to establish effective therapeutic recommendations. We here describe the largest retrospective cohort of pediatric LFS SHH-MB patients to date and their clinical outcomes.
PATIENTS AND METHODS: N=31 patients with LFS SHH-MB were included in this retrospective multicenter study. TP53 variant type, clinical parameters including treatment modalities, event-free survival (EFS) and overall survival (OS), as well as recurrence patterns and incidence of secondary neoplasms, were evaluated.
RESULT(S): All LFS-MBs were classified as SHH subgroup, in 30/31 cases based on DNA methylation analysis. The majority of constitutional TP53 variants (72%) represented missense variants, and all except two truncating variants were located within the DNA-binding domain. 54% were large cell anaplastic, 69% gross totally resected and 81% had M0 status. The 2-(y)ear and 5-(y)ear EFS were 26% and 8,8%, respectively, and 2y- and 5y-OS 40% and 12%. Patients who received post-operative radiotherapy (RT) followed by chemotherapy (CT) showed significantly better outcomes (2y-EFS:43%) compared to patients who received CT before RT (30%) (p<0.05). The 2y-EFS and 2y-OS were similar when treated with protocols including high-dose chemotherapy (EFS:22%, OS:44%) compared to patients treated with maintenance-type chemotherapy (EFS:31%, OS:45%). Recurrence occurred in 73.3% of cases independent of resection or M-status, typically within the radiation field (75% of RT-treated patients). Secondary malignancies developed in 12.5% and were cause of death in all affected patients.
CONCLUSION(S): Patients with LFS-MBs have a dismal prognosis. This retrospective study suggests that upfront RT may increase EFS, while intensive therapeutic approaches including high-dose chemotherapy did not translate into increased survival of this patient group. To improve outcomes of LFS-MB patients, prospective collection of clinical data and development of treatment guidelines are required

Climate change has become a global emergency, which mental health effects are increasingly being described and understood. Children and adolescents, especially those in low income countries and minority communities, are particularly vulnerable to experience the worst impacts of climate change now and in the coming decades. Our group of early career mental health clinicians and researchers in nine culturally and socioeconomic different countries across three continents initiated a global, online discussion about the effects of climate change on the mental health of children and adolescents, based on literature and our professional experience. We identified a paucity of research and psychiatric education on the topic, and a need to advance global and local efforts in this direction. We also identified three main domains of mental health impact of climate change: direct, indirect, and through physical conditions. Our work offers a preliminary, up-to-date overview of the consequences of climate change on the mental health of children and adolescents, and provides recommendations to advance policies, public health efforts, research, education, and clinical care in the emerging area of 'Climate Psychiatry'.

Background: Significant racial and ethnic disparities exist in the community in underprescribing analgesics for pain and overprescribing antipsychotics for behavioral symptoms in persons with dementia. In hospice these drugs are commonly used to provide comfort, but little is known about prescription patterns in minoritized populations. We aimed to identify prescribing patterns in minoritized racial and ethnic groups among persons with living advanced dementia in home hospice.
Method(s): A cross-sectional study of 6,874 participants with advanced dementia from eight hospices across the United States. Demographics, antipsychotic (typical, atypical) and analgesic (opioid, non-opioid) prescriptions at admission, days of prescription use in hospice and length of stay were collected from electronic records. Descriptive statistics were calculated and hurdle regression models estimated to examine the association between race/ethnicity and prescription rates for each drug (days of drug use per 100 person-days).
Result(s): Participants were 10.7% Black, 34.8% Hispanic, 51.1% white, and 3.3% from other racial and ethnic groups. On admission, Hispanics and Blacks had similar rates of antipsychotic prescription that were lower than whites (11.9% & 12.3% vs 16.8%) and Hispanics had substantially lower non-opioid analgesic prescription vs Blacks and whites (23.3% vs 36.0% & 37.3%); During the hospice stay, Hispanics were prescribed antipsychotics (atypical RR =1.03, 95 % CI: 1.02-1.04; typical RR:1.04, 95% CI: 1.01-1.07) and analgesics (opioid RR =1.03, 95% CI: 1.02-1.04; non-opioid RR = 1.03, 95% CI = 1.02-1.03) for more days than whites. Blacks were prescribed analgesics (opioid RR =1.09, 95% CI 1.08-1.11; non-opioid RR = 1.01, 95% CI: 1-1.02) for more days than whites.
Conclusion(s): Disparities in analgesic and antipsychotic use on admission amongst Blacks and Hispanics were found, yet hospice narrowed this gap significantly. While less likely to be prescribed opioids, Blacks and Hispanics had more person days on analgesics overall. However, there was divergence in antipsychotic use over time between groups that requires further investigation given the controversial role of antipsychotics in management of dementia symptoms

Current clinical literature and supporting animal literature have shown that repeated and profound early-life adversity, especially when experienced within the caregiver-infant dyad, disrupts the trajectory of brain development to induce later-life expression of maladaptive behavior and pathology. What is less well understood is the immediate impact of repeated adversity during early life with the caregiver, especially since attachment to the caregiver occurs regardless of the quality of care the infant received including experiences of trauma. The focus of the present manuscript is to review the current literature on infant trauma within attachment, with an emphasis on animal research to define mechanisms and translate developmental child research. Across species, the effects of repeated trauma with the attachment figure, are subtle in early life, but the presence of acute stress can uncover some pathology, as was highlighted by Bowlby and Ainsworth in the 1950s. Through rodent neurobehavioral literature we discuss the important role of repeated elevations in stress hormone corticosterone (CORT) in infancy, especially if paired with the mother (not when pups are alone) as targeting the amygdala and causal in infant pathology. We also show that following induced alterations, at baseline infants appear stable, although acute stress hormone elevation uncovers pathology in brain circuits important in emotion, social behavior, and fear. We suggest that a comprehensive understanding of the role of stress hormones during infant typical development and elevated CORT disruption of this typical development will provide insight into age-specific identification of trauma effects, as well as a better understanding of early markers of later-life pathology.